CA2179402A1 - Indoline derivatives, method of preparation and their use as pharmaceuticals - Google Patents

Abstract

A compound of formula (I), wherein R1 is hydrogen, halogen or C1-6 alkyl; R2 is a group of the formula (I) -CR3R4(CH2)pNR5COR6; R3, R4 and R5, which may be the same or different, are hydrogen or C1-6alkyl; R6 is C1-6alkyl or C3-7 cycloalkyl; n is an integer of 2, 3 or 4; p is an integer of 1, 2, 3 or 4; and pharmaceutically acceptable salts and solvates thereof. A compound of formula (I) is useful in the treatment of conditions associated with a disturbed functioning of the melatonin system.

Description

WO 95117405 ~ r~ .c ~` 21 794~2 INDOLINE DER~.Y~:TIyEs~ METHO~ OF PREPARATION AND~.~EIR USE ~S 'PHARMAcEuTICALS
This invention rslates to tricyclic indoline derivatives, to ~uces~es for their ,Ult~JdldiiUII, to IJIldl~l A~ltir~l wlll,uOailiu~ cu"t..;"i"g them and to their medical use.
The invention thus provides compounds ûf fonmula (l) ` ~ J
~(CHJn R2 1û wherein R1 j5 hydrogen~ halogen or C1 6 alkyl;
R2 is a group of fommu~a -CR3R4(CH2)pNR5CoR6;
R3, R4 and R5, which may be the same or different, are hydrogen or C1~alkyl;
R6 is C1 6alkyl or C3 7 cycloalkyl;
n is an integer of 2,3 or 4;
p is an integerof 1,2,3 or4;
and ~ul~d,,,,ac~vutically ~ le salts and solvates (e.g. hydrates) thereof.
lt will be d~u~ulvuidL~d that in fommula (l) h~ illdL.UJV the substituent R1 maybe attached at either available position on the phenyl portion of the tricylic ring.
As used herein, an alkyl group may be a straight chain or branched chain 2û alkyl group. Examples of suitable alkyl groups include C14 alkyl groups, for examp~e methyl, ethyl and isopropyl groups. A preferred alkyl group is methyl.
A halogen substituent may be, for example, fluorine, chlorine, bromine or iodine.
R2 preferably ,~ se"b a group -CR3R4(CH2)pNHCoR6 wherein R3 and R4 each illJe:,uvll~;lvlllly represent hydrogen or C1 3 alkyl (e.g methyl), p is an integer of 1 or 2, especially 1, and R6 is C1 3 alkyl (e.g. methyl) or C3 5 cycloalkyl (e.g. cyclopropyl or cyclobutyl).
Examples of the group R1 include hydrogen, halogen (e.g. chlorine) and C1 3 alkyl (e.g. methyl).
3û A preferred group oF compounds of the invention are compounds of formula (la) WO 95/1740~i 2 t 7 9 4 ~ 2 . ~ c - ~

o~ ~NJ (1a) and ~ ldl~ ly r ~ salts and solvates (e.g. hydrates) thereof, wherein R1 and R2 are as defined h~ duuve It is to be ulldelaluùd that the present invention eovers all wlllbilldLiulla of5 partieular and preferred groups deseribed hel _;. IdbOI~e.
Partieular eompounds aeeording to the present invention inelude:
N-[2-t273l8~9-Tetrahydro-7H-pyrano[2~3-g]indol-1yl)-ethyl~ dlllide~
N-[2-(2,3,7,8-Tetrahydro-1 H-furo[2,3-g]indol-1 -yl)-ethyl~-A~
N-[2~5-Chloro-2,3,7,8 tut, dl "/dl u-1 H-furol2,3~]indol-1 -yl)-ethyl~-dLt~ld, ~ lide;
1û Cy~,lu,u,uf,a,,6w,L,~yl;L aeid [2~2,3,7,8-tetrahydro-1H-furol2,3-g]indol-1-yl)-ethyl]-amide;
and ~,~ ,d" "aceutieally A~ salts and solvates thereof.
A partieularly suitable eompound aeeording to the present invention is N-[2-(2,3,7,8-Tetrahydro-1H-furo[2,3-g]indol 1 yi) ethyl]-~ "i~1~ and 15 ~JI lal ~ e, Itir~lly ~ salts and solvates thereof.
rlldlll-~-e'ltir~lly A~ 'I-IP salts of the eompounds of formula (I) inelude those derived from ,Ulldllll~r~ll 'l~ d~ le inorganic and organic acids.
Examples of suitable acids include h~.llu~,lllulil,, h~,.lluLIullli-,, sulphuric, nitric, perehloric, fumaric, maleie, ~l lua~ul i", glyeollic, lactic, salicylic, succinic, 2û toluene-p-sulphonic, tartaric, aeetie, eitrie, Illetlldll6aulphonicl formic, benzoie, malonie, l ~a~l ," ,dl~"e-2-sulphonie and bél l~el lesulphonie aeids. A partieularly suitable IJIldlll'~ arv~ salt of the eompounds of forrrlula (I) is the I ,JJ~ u~.hlu, ide salt. Other aeids sueh as oxalie, v~hile not, in themselves iJI Idl 1 1 1;~ l ltir5~lly &~ le, may be useful as i, I(el l l l ~ ' in obtaining the 25 eompounds of the invention and their ,Ulldlll'~'l' lly ~.. t.l.~ I.l~ aeid addition salts.
nuf~..ell~s heleilldrlel to a eompound of formula (I) ineludes the eompound and its plldlllld~utieally ~ le salts.
The eompounds of formula (I) may eontain at least one a~)."",_',ic earbon 30 atom and may exist as ;~lele~;3~111ela. The eompounds of formula (I) thus WO 95/17405 ~ T ~ -n

2 ~ 7~402 include the d- and l-isomers and mixtures, for example racemic mixtures, thereof.
The compounds of forrnula (I) are of use in the treatment of disorders which arise from a disturbed functioning of the melatonin system. . In particular the 5 compounds of formula (I) may be used in the treatment of ~Ilu~ vluu; 3l disorders, especially in the elderly pop~ , glaucoma, cancer, ~sy~l ' i-.
disorders, ~atau~JuluaiS, neu,u~yal~al ti~o diseases or neu~ual,~u~,i"a disorders arising as a result of or influenced by the melatonin system.
Ch~ u~ ivl~ I disorders include seasonal affective disorders (SAD), 10 primary and secondary insomnia disorders, primary and secondary I l"yal a~l ", lid disorders, sleep-wake schedule disorders (including advanced phase type, delayed phase type, ~;..u, yd, 1;_3~ type and frequently-changing type) and other ~y~su"" lida, especially those caused by ageing, d~ll lal l~;d:~, blindness shift work and by rdpid time-zone travel, commonly known as jet lag.
Cancers which may be treated with a compound of formula (I) include solid tumours, e.g. " ,ol~. ,ull,aa and breast Cal ui, lulllaa ~ sy.,l l;d~ . disorders which may be related to altered melatonin function or influenced by melatonin and circadian rhythms include mood disorders (including bipolar disorders of all types, major de~,,a~:,iun, dysthymia and other 20 de,c.(~ disorders), psy~,l,ùd~ti~l~ substance dt~a".l~nc~ and abuse, anxiety disorders (including panic disorder, ay~ld~JllOLia, social phobia, simple phobia, ub~.i9;io compulsive disorder, post-traumatic stress disorder and ge"a,dlised anxiety disorder), s..l,i u~Jllla"ia, epilepsy and epileptic seizures (includinggrand mal, petit mal, myoclonic epilepsy and partial seizures), disorders of 25 involuntary IlluO~ all~ (including those due to Pd~killaun'a disease, and drug-induced involuntary ~u~u"~ ts) and dalllal ~ias (including primary degel~ald~i~/e dementia of the Alzheimer type).
Neulud~yanal "~e diseases which may be related to altered melatonin function or influenced by melatonin and biological rhythms include multiple 30 sclerosis and stroke.
Neu,ua".lu~,,ille disorders which may be related to altered melatonin function or influenced by melatonin and biological rhythms include peptic ulceration, emesis, psoriasis, benign prostatic l,),u~,~,lasia, hair condition and body weight. Particular neu, ual Id~u i"e disorders which may be treated include35 those relating to the regulation of reproductive maturation and function include WO ~5117405 ~ i" ' 2 1 7 9 4 0 2 idiopathic del3yed puberty, sudden infant death, premature labour, inf~rtility, _. f~ el l lal laL ual syndrome (including late luteal phase dysphoric disorder) and sexual dysfunction (including sexual desire disorders, male erectile disorder, post-menopausal disorders and Drgasm disorders). The 5 compounds may also be used to Illall, ~'~'^ breeding cycles, body weight, coatcDlour and ~ir " , of c, lcc~r~ihl~ hosts, includin6 birds, insects and mammals. The compounds of formula (I) may also have sedative, anti-i"f: ..,.., y and analgesic effects, e~fects on the microcirculation and immunomodulant e~fects and may be useful for the treatment of l.y~Jellel laiull,1û migraine, cluster headache, arthritis, regulation of appetite and in tne treatment of eating disorders such as obesity, anorexia nervosa and bulimia nervosa.
There is thus provided in a further aspect of the invention a compound of formula (I) for use in therapy, in particular in human medicine. It will be a,~llJI e~,k~t~ that use in therapy embraces but is not l~e~ ~aal ily limited to use of 15 a compound of fommula (I) as an active therapeutic substance.
There is a~so provided as another aspect of the invention a compound of fommula (I) for use in the ,." el~al d~iUI I of a " ,ediw" ._. It for use in the treatment of conditions ~ d with a disturbed functioning of the melatonin system.
In an dllelll.~til~, or further aspect of the invention there is provided a 20 method for the treatment of a mammal, including man, ~",~,, iail Iy ad,.,i., a~i~n I
of an effective amount of a compound of formula (i), in particular for the treatment of conditions A~.50~ d with a disturbed functioning of the melatonin system.
It will be a~Jle-.id~ed by those skilled in the art that reference herein to5 therapy and treatment extends to prophylaxis as well as the treatment of ldLli..l ,ed symptoms.
While it is possible that, for use in therapy, a compound of formula (I) may be ad~llill;_t~,.e~ as the raw chemical it is preferable to present the active ingredient as a ~,I.a.",-dceutical formulation.
The invention thus fur~her provides a ~,l lal ~ 1 .A~ ti_~l fonmulation c.u. .. yl i .i. ,9 a compound of fommula (I) together with one or more ,OI,a",-~e~" lly carriers therefor. The carrier(s) must be 'ar,~ ' in the sense of being c~ ~ "~ le with the other i"yl ediel lt~ of the formulation and not deleterious to the recipient thereof.

WO 9~/17405 P~
~ 21 79402 There is further provided by the present invention a process of preparing a ~ dl~ " ' fommulation, which process cu~ nic~ mixing a compound of fommula (i) with one or more pl Idl 1 " ~ Ar~ carriers therefor.
rl Idl~`` ''`~' ~;'`AI fommulations include those suitable for oral, rectal, vaginal, 5 nasal, topical or pal t:~ 1 al (including intramuscular, subcutaneous and intravenous) d~lllillialld~iùn or in a fomm suitsble for a.ll.-i.. ' ~'k~n by inhalation or insufnation. The formulations may, where ~,u~upri , be cull~ iel,~l~
presented in discrete dosage units and may be prepared by any of the methods well known in the art of phammacy. All methods include the step of bringing into10 a~ the active compound with liquid carriers or hnely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
For oral ~JI~ dliUI " the ~JI lal ~ P ItirAI cu"~ , may take the form of, for example, tablets or capsules prepared by conventional means with 15 pl,d""~ y ~ excipients such as binding agents (e.g.
geldti";_ad maize starch, pol~v;"y~,J"~'' )e or l,ydlu~,vlu~"rl OS8); hllers (e.g. Iactose, miwocrystalline cellulose or calcium pllCIa,ul. ~.); lubricants (e.g. magnesium stearate, talc or silica); J;.1 _ all~:~
(e.g. potato starch or sodium starch glycollate); Ot wetting agents (e.g. sodium2û lauryl sulphate). The tablets may be coated by methods well known in the art.Liquid ~ pdlati~-s for oral ad,,,;.,;~t~dtiù,, may take the form of, for example, solutions, syrups or susp~, laiOI~a, or they may be presented as a dry product for cu,, ~ , with water or other suitable vehicle before use. Such liquid pl~::pdl_" la may be prepared by conventional means with pl~d",~ a~ y 25 ~r~ P additives such as suspending agents (e.g. sorbitol synup, methyl cellulose or h~luy~slld~t:d edible fats); emulsifying agents (e.g. Iecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl-D-I ,;. ' u,~yb~. _ or sorbic acid).
For topical a~..i, lialldliul I in the mouth, the ~ ~ 5 may take ths form 30 of buccal or sub-lingual tablets, drops or lozenges fommulated in cu"~_" )dl manner.
For topical ~ - ' d~iull to the epidermis the compounds may be formulated as creams, gels, ointments or lotions or as a lldlla~lllldl patch.
Such ~,u. "~ , la may for example be formulated with an aqueous or oily base WO9S/17405 2 1 7q402 1 .,~ ~c.. " ~

with the addition of suitable U ,i~";"g, selling, emulsifying, stabilising, di~ ail 1~, suspending and/or colouring a~ents.
The compounds of the invention may be formulated for p~dl t:l .h. dl ddlllill' ~.dliUII by injection, conveniently intravenous, intramuscular or i; 51Ih~l1' I~ UI~S injection, for example by bolus injection or continuous intravenous infusion. Fommulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose cc"~di"~:,a, with an added preservative. The ~ l,u~ l la may take such forms as sua~,~nsions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents 10 such as suspending, stabilising andlor d;~ lailly agents. Altematively, the active ingredient may be in powder fomm for cu,, ~ ~in~ with a suitable vehicle,.9. sterile pyrogen-free water, before use.
The compounds of the invention may also be fommulated in rectal wlll~Ju~i~iulla such as c~, idS or retention enemas, e.g. ~,ullIaillillg 15 conventional c~ bases such as cocoa butter or other glyceride.
Pessaries for vaginal ddl l lil ,;~ t, dliUI I may be formulated in a similar manner.
For intranasal d~lllill;_'~d~iU~I the compounds of the invention may be used, for example, as a liquid spray, as a powder or in the foml of drops.
For a~l"i";~I,dliu" by inhalation the compounds according to the invention 20 are cull./u"ie:"~y delivered in the fomm of an aerosol spray pll:a~ dIiùl~ from pressurised packs or a nebuliser, with the use of a suitable propellant, e.g.
di~.llluludinuulull~_;lldlle, trichlorofluc.,u",~ll,d"e, di~ lul~ clnUUlU~Illdlle, carbon dioxide or other suitable gas. In the case of a pressurised aerosol the dosage unit may be d_'u.lllill~d by providing a valve to deliver a metered 25 amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated ~"'..;.,i"~ a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
Any of the ~JIldlll~Ar~lti~Al culll~usiliulla described above may be presented in a cu",~ iùnal manner A~o~ d with controlled release fomms.
The active ingredient may conveniently be presented in unit dose form. A
convenient unit dose fommulation contains the active ingredient in an amount of from about 0.01 mg to about 200mg.
It will be d~ ' ' that the precise dose dll~llil 1' ' ~d will depend on the age and condition of the patient, the particular compound used and the frequency and route of d~lllill' d~iun and will u~timately be at the discretion of WO9S/17405 ~ ` 2 ~ 794~2 ~ C~

the attendant physician. The compound may be ddlll;~l' ' ed in single or divided doses and may be dd~ll;ll;.~t~..ed one or more times, for example 1 to 4times per day.
A proposed dose of the compounds of the inYention for oral, rectal, vaginal, 5 intranasal, topical or pdl6~1 dl ad~ll;l 'Id~iulI to man (of ~ lU~il 'y 70kg bod~. ~ t) for the treatment of w~ a r - ' with a disturbed functioning of the melatonin system is 0.01 to 200mg of the active ingredient per unit dose which could be a~"i, ' ~d, for example, 1 to 4 times per day.
For oral dd~llil 1' ' dliUt) a unit dose will ~ f~..dLly contain from 0.1 to 200mg of the active ingredient. A unit dose for pdl t:l 1' dl ddnlil 1' ' d~iUI) will ~Fu. dLly contain 0.1 to 5 mg of the active ingredient.
Aerosol formulations are preferably arranged so that each metered dose or 'puff delivered from a pressurised aerosol contains 0.2 mg to 2 mg of a compound of the invention, and capsules and cartridges delivered from an insufflator or an inhaler, contain 0.2 mg to 20 mg of a compound of the invention. The overall daily dose by inhalation with an aerosol will be within the range 1 mg to 100 mg. Adlllilliatld~iull may be several times daily, for examplefrom 2 to 8 times, giving for example 1, 2 or 3 doses each time.
Dosages of the compounds of the invention for recta~, vaginal, intranasal or topical adl l lil liat~ dtiul ~ are similar to thûse for oral a~ "i"i~l, dliUI 1.
The compounds of the invention may, if desired, be ddl l lil ' ed in COlllLlilld~;ull with one or more other therapeutic agents such as a hypnotic ordl' ~ adll~ agent, or an anti-cancer agent such as Idlll~ Jllel~ or in co,nL,i"dl;o" with radiation therapy to treat cancer.
The w~lL;(ld~iulls refenred to above may Cull~ iell~ly be presented for use in the form of a ~JIIdlll~ r~l formulation and thus pl,d""~ ltic~l formulations wlll,uli~ a compound of fommula (I) to~ether with at least one other therapeutic agent and one or more ~lldllll;l~ carriers therefor comprise a further aspect of the invention.
3û When compounds of fonmula (I) are used in cu,,,Li,,d~i~n with other therapeutic a~ents, the compounds may be ~.11,,;,, ed either sequentially or simuitaneously by any cul ,~,. I;el ,I route.
When such colllL,illd~iùl~s are employed the dose of each cclll~Jùl~elll of the cu~ ill I will in general be that employed for each wlllpûllel)~ when used alone.

w09sll740s ~ 2 1 79492 ~ nl~n Compounds of fo,-mula (I) and p,',a~ æ~ ~' 'Iy a~ salts and solvates (e.g. hydrates) thereof, may be prepared by methods known in the art for the i~le la, I of analogous cnmrol~n~C ~n particular the compounds of fommula (I) may be prepared by the methods outlined below and which forrn a 5 further aspect of the invention. In the following ~IU~,éS~s, R1, R3, R4, R5, n~nd p are as defined for fommula (I).
According to one general process (A) a compound of fommula (I) may be prepared by acylation of a compound of fommula (Il) R' O ~/'1~ N (Il) (CH2)n CR3R~(CH2)pNHRs Suitable acylating agents which may conveniently be used in the above process include acid rJ"Il,;~ ,ës and acid halides. The reaction is CC~ iell~ly effected in a suitable solvent such as an ether (e.g. diethyl ether, tetrahydrofuran or dioxan), a IIJ~uuci~iJu~l such as toluene or a ~ uyel ~' I,;."u~,a",on (e.g. Jil,lllulu,,,e~,a,,e), preferably in the presence of a base such 15 as pyridine or a tertiary amine (e.g. ,,,;;~,,"u"Jl~ l..."i"e), at a temperature in the range of û to 100C, preferably 0 to 20C.
Compound$ of fommula (Il) in which R5 is hydrogen may cc~ .liel~t'y be prepared by the reduction of compounds of formula (Ill) - R' o,~ (111) (CH2)n CR3RC(CH2)p,,CN
20 (wherein the dotted line indicates an optional double bond). The reduction may culli~.,ie, 'l~ be effected using a boron hydride reducing agent such as borane-~ ,dl,~ Pr, complex in an ether solvent (e.g. h~dl~J~"~ r ~ran) optionally in the presence of a suitable acid (e.g. trifluoroaoetic acid, hy~,lu,,l,lu,i~, acid or the like) at a suitable temperature, for example from OD to 100C. A'' , ' .~ly, the25 reduction may employ catalytic l,J~"uyel,d~;ul, in the presence of a noble metal catalyst, such as platinum, palladium or the like, in a suitable organic solvent;

WO95117405 ~ 21 79402 1~1/~ ,c .~,.
" . ~

such as an alcoholic solvent, e.g. ethanol, conveniently at a h.,~ ' Ire in the range of 0 to 1 00C, aptly at room l~ Jt51 ' Ire.
Compounds of formula (Il) in which R5 iS C1 6 alkyl may be prepared by N-alkylation of compounds Of formula (Il) in which R5 is hydrogen using standard 5 procedures.
Compounds of formula (Ill) may conveniently be prepared by alkylating compounds of formula (IV) ~(CH~ (IV) using an agent HalCR3R4(CH2)p 1 CN in which Hal is a halogen atom (fluorine, 10 bromine, chlorine or iodine), suitably in the presence of a base. The alkylation may be carried out under standard ~llditiùll5. For example, the reaction may be effected in a ketonic solvent in the presence of an alkali or alkaline earth metal carbonate (e.g. potr~C~illm carbonate) at an elevated le~ ' Ire (e.g.
under reflux). A'' ll '',~uly, the reaction may be effected in dimeth~;' ",~",ide 15 in the presence of an alkali metal hydride (e.g. sodium hydride) at about ambient l~ re.
Compounds of fommula (IV) in which the dotted line indicates a double bond may be prepared by the decd, bùA~ t;JI I of compounds of fommula (V) (CH~C02H
Thus, compounds of formula (V) may be decdlbùA~ . by heating the compounds at a very high lel~ re (e.g. at about 250C), optionally in the presence of copper and a suitable copper salt, such as copper (I) oxide, cuprous oxide and the like.
Compounds of fommula (IV) in whiCh the doffed line indicates a double bond may be wnverted to the ~llts~uu~ldi~l~ s8turated analogues of formula (IV) by reduction, for example using the UJ~"" .Is described above to prepare the compounds of fommula (Il) from compounds of formula (Ill).

wogs/l7405 ~ ~ ~ ; 2 ~ 794 02 r~ c - ~

Compounds of fommula (V) may be prepared by the C~ l;__L;JI, and de~alel - ' I of compounds of formula (\/I) ~ N3 ~ (CH2)n (wherein R is a C1~ alkyl group, e.g. methyl). The cy.,~ ti~" reaction may 5 conveniently be effected by heating (Vl) to reflux in an aromatic ll,.' uw,~u,, solvent (e.g. xylene). Conversion of the so-formed ester to the cc",~ ,ullJi, acid of formula (V) involves routine hydrolysis, for example using a base such as a hydroxide (e.g. sodium hydroxide) at an elevated t~l"~ re (e.g. under reflux).
Compûunds of formuia (Vl) may be prepared by treating compounds of fommula (Vll) R1 ,,~ CHO
0~ (Vll) I (CH2)n with an alkyl ~ in the presence of a strong base (e.g. potassium tert-butoxide) at a It:l ",~. re of from -20 to +1 0C.
1~ Compounds of fommula (Vll) are either known compounds described, for ~xample, in WO 86107056 or may be prepared by methods analogous to those described therein.
Altematively compounds of fommula (IV) in which the dotted line indicates a double bond may be prepared by c~ iu" of compounds of formula (Vlll) R' ~ ~OR
l(CH2)n COCX3 wherein X (~ylelaellb a halogen atom (e.g. fluorine) and R is a C,~alkyl group, such as methyl or ethyl. P~e:pcll~l~iul~ of compounds of formula (IV) typically WO9S117405 ,, . ~ -. 2 1 79~02 ~ o l~n involves addition of a solution of wmpounds of fommula (Vlll) (suitably in a ~,1 ,lu, i, ~ ' ~ organic solvent such 8S di~ l ul I l~tl lal ,e"~ lul u~l ,c."a or the like) to an acidic medium, such as ~,..lag~, ' ' acetic acid andlor acetic anhydride optionally in a ulllo(i, ' ~ organic solvent as described above, Suitably the 5 addition is canried out at ûC under an inert ~ llu~ such as nitrogen. The reaction may be ,u, uy, ~ased by allowing the reagents to reach room k~ re, and stinring for about 18 to 2û hours. The resulting mixture is generally treated vlith a base, such as an alkali metal hydroxide, prior to extraction of desired wmpounds of fommula (IV).
1û Compounds of fonmula (Vlll) are suitably prepared by acylation of wmpounds of formula (K) R' O~NH~ (IX) . OR
(CH2)n employing suitable acylating agents such as acid anhydrides and acid halides.
Suitably a l,aluy~r ' ~ acetic anhydride (aptly trifluoroacetic anhydride) in a ,llluli~ organic solvent as described above is added to a solution of a wmpound of formula (IX) in a basic solvent, such as triethylamine and the like.
Generally the addition is carried out at ûC under an inert d~lllos,ullt~ such as nitrogen.
2û P~ Jal~Liull of wmpounds of fonmula (IX) suitably employs known starting materials of fommula (X) shown below, v,/hich starting materials can be preparedacwrding to J. Heterocvclic Chem.. (1973), Vol 1û(4), page 623. Compoun~s of fommula (X) (J~NH2 (CH2)n WO 95~17405 , , . , 2 ~ 7 9 4 0 2 ~ C '--~A ~

are aptly reacted with a suiSable acetal d~rivative, co" ~s. ,~ in the presence of a base (an alkali metal carbonate being an example of an ~ , u~, idlt~ base), with heating over a prolonged period of time (such as 40 to 65 hours) at an elevated h,.~ re in the range of 90 to 110C, in order to yield compounds of fonmula (IX).
Compounds of fonmula (I) in which R~ Jl.,a~l lti. halogen may be prepared via compounds of fonmulae (Il), (Ill) and (IV) wherein R' ~ s_.~ts halogen employing process steps su~ak,ll" 'l~ as ~Itzlt7illb_fult: described. Suitably compounds of fommula (IV) in which R' I~,yl~a~l,tS halogen are prepared from compounds of formula (Xl) wherein R~ a~lltSa halogen and the dotted line indicates an optional double bond.
~ (Xl) (CH2)n CHO
Aptly a compound of fonmula (Xl) is dissolved in an organic solvent, such as an alcoholic solvent, acidified, and the mixture subjected to stinring and refluxins for a suitab~e length of time to yield a ,u, ,~ ,u, n~i"~ compound of fommula (IV).
Cu"~ ly a compound of formula (Xl) wherein R~ ael Ita halogen as described above is prepared from a cull~,,,u,,.li,l~ compound of fonmula (Xl) wher~in R' ,~ .s~"ts hydrogen by l ,c.loge~ Jlùy;. l~ suitable 1 Idlùg~rlcliil ,9 agents and techniques.
Suitably r,ompounds of formula (Xl) wherein R' It~ a~ a hydro~en as described above may be prepared from compounds of fomnula (IV) wherein R' ac~ hydrogen by reaction of the latter with an c,~ ,u~, i ' anhydride in an acidic medium.
According to a further ~ u~ _. ll of the present invention, there is provided a further general process (B) wherein a compound of fonmula (I) may be prepared from a compound of fommula (Xll) WO 95117405 ~ , , , r~.l/l!,l . ~'C l-~A
21 7~02 ,~ (Xll) tCH2)n CR3R4(CH2)pN(CoR~)2 suitably by stirring for several hours (17 to 19 hours) in a basic medium, cu",/~ "t'y an alkali metal hydroxide or the like, under an inert r' llua such as nitrogen, followed by refluxing for 1 to 2 hours.
Aptly a compound of formula (Xll) may be prepared by acylation of a compound of fonmula (Il) e~ JIû,/;,l~ acylation techniques suL.sldl~ti- Il; as h~l e :il ,L,_'u, t, described.
According to a yet further e~llJu~ 3~ll of the pr2sent invention, there is provided a general process (C) whereby a compound of formula (I) may be 1 û prepared by alkylating a saturated compound of formula (IV). Suitably alkylation is achieved by refluxing a compound of fonmula (IV) together with an alkylating agent over several days. Suitable alkylating agents include HalCR3R4(CH2)pNRsCOR6 (wherein Hal, R3, R~, R5, R6 and p are as l~ _'v . defined), ANR5CoR6 wherein A l ~:~n t:a~ t~ a 2-1 l,_, llL~ d alkyl chain or the like.
Compounds of formulae (Il) - (IX), (Xl) and (Xll) are noYel i"'~, IIIC:didi~s and represent further individual aspects of the present invention. Compounds of fonmula (IVa) represent a further particular aspect of the invention.
O "l, ~J (IVa) According to another general process (D), a compound of formula (I) may 20 be prepared by subjecting a protected derivative of a compound of formula (I) or a salt thereof to reaction to remove the protecting group or groups.
Thus, according to a further aspect of th2 invention, the following reactions may according to process (D), if desirable and/or if necessary, be carried out in any dlJ, W Ul~l ' ' sequence:
25 (i) removal of any protecting groups; and WO 95rl7405 2 1 7 ~ 4 0 2 P~ .'0: ~

(ii) wnversion of a compound of formula (I) or a salt thereof into a ~lla~ 'Iy ~ salt thereof.
Thus, at an earlier stage in the ~ Jald~iùn of a compound of formula (I) it may have been necessary and/or desirable to protect one or more sensitive 5 groups in the molecule to prevent IJ"u~_:. dbl~ side reactions.
The protecting groups used in the ~ Jal d~iUI I of compounds of fommula (I) may be used in wll~u.lliulldl manner. See for example 'Protective Groups in Organic Chemistr~ Ed.J.F.W. McOmie (Plenum Press 1973) or 'Protective Groups in Organic Synthesis' by Theodora W Greene (John Wiley and Sons 1991) According to another general process (E), compounds of formula (I) may be prepared from other compounds of formula (I) by i~ ,u~J_.~iull reactions. In particular, acid addition salts of compounds of formula (I) may be prepared froma c~" ~a~vl Idi~ 19 compound of formula (I) by suitable acid treatment, for example -dddition of a suitable acid, such as ll)~uulllù~i~. acid, generaly in the presence of an organic solvent such as an alcohol or ester. Aptly the reagents may be stirred at room le~ re for a cc",.-. ,;_.,l length of time. A' Il.Jt~cly, an acid may be added dropwise to a solution of a compound of formula (I) in an a,u,ulu~Jli organic solvent as described above, optionally under an inert : ' llua,~ such as nitrogen.
Where it is desired to isolate a compound of the invention as a salt, for example as an acid addition salt, this may be achieved by treating the free baseof general fommula (I) with an a,u,ulu~ ~ acid, preferably with an equivalent amount, or with creatinine sulphate in a suitable solvent (e.g. ethanol).
Compounds of the invention may be isolated in ~,o~.;,.t;."~ with solvent molecules by cry~ " ~ from or evaporation of an a,u~lupl idl~ solvent.
Individual er,a,l~iullle:,a of the compounds of the invention may be prepared from laut Illal~s by resolution using methods known in the art for the ~,ualL~ia~
of racemic mixtures into their constituent e:llalltiullrcla, for example using chiral HPLC.
As well as being employed as the last main step in the ~, ~ual ali iC
sequence, the ~eneral methods indicated above for the ~ ,ud,aliù~, of the compounds of the invention may also be used for the introduction of the desired groups at an i"t~ dial~: stage in the ~ ,ual dtiUI) of the required compound. Itshould therefore be a~ ' ' that in such multi-stage ~, u~:Sa~5, the WO 95117405 r ~ ~ c ~ n 2 1 7~402 sequence of reactions should be chosen in order that the reaction cu, .~;ti~ "s do not affect groups present in the molecule which are desired in the final product.
The invention is further illustrated by the following Examples which should not be constnued as cqnstituting a limitation thereto. All temperatures are in C.
THF means h.tidl,ydl-furan. EtOH means ethanol. EtOAc means ethyl acetate.
DMF means di~Y~ a~lida. NH3 means Cullllllel 'Iy available aqueous ammonium hydroxide. TFA means trifluoroacetic acid. TFM means trifluoroacetic anhydride. Dried means dried over anhydrous sodium sulphate (unless otherwise stated). Clllull _ a~ was pc,F~.""ed on silica (Merck 9385 unless otherwise stated). System A is di~lllu~ull,_~ ll_/u::ld~ ?qllPollc ammonia. T.l.c. means thin layer ul.,u,, _ atJlly on silica gel. The n.m.r.
analysis was conducted at 250mHz.
Il Itel 11 1eu i~
2-~izido-3-(2.3-dihvdro-benzofuran-5-vl)-acrvlic acid methvl ester To a cold (-10C) stirred solution of potassium tert-butoxide (6.069) in dry methanol (40ml) was added dropwise a mixture of 2,3~1;1lydluLJell~uf~llal~-5-wl~ùxdldel~Jdè (29) and methyl ~ (6.219). The mixture was stirred for 1h at -10C and then stored at 0C for 18h. The resulting pale yellow microcrystals were collected by filtration to give the title comPound (3.129) m.p. 77-80C.
Il t~ . " ~ 2 7.8-Dihvdro-1 H-furo~2.3-qlindole-2~a, ~u,~vlic acid A solution of ll l I l ledi_:~ 1 (3.19) in xylene (350ml) was heated to reflux for 2h.
The cooled mixture was washed with water (100ml) and then the aqueous layer extracted with xylene (50ml). The combined organic phases were dried and evaporated and the residue dissolved in ethanol (4ûml). 2N Sodium hydroxide was added (20ml) and the mixture heated to reflux for 2h. The ethanol was e.~,.u, and the mixture extracted with ether (2x5ûml). The aqueous layer was then acidified 3nd extracted with EtOAc (2x75ml). The dried extracts were G.r..~.,ul ' ;; to give the title comr~ound as a yt .1 'v,a"ge solid (878mg) m.p.
160C (chars) 213C (dec.).
Il, Ill_~idte 3 WO 95/17405 ~ 7n . . .

7.8-Dihvdro-1 H-furor2.3~1indole ~ ' ", 'i~ 2 (875ms) was placed in a pre-heated Woods metal bath (~.
250C) for 2min until CO2 evolution had ceased. The material was pre-r~bsorbed onto silica ~el and then ,lllulll ,, d~ d (359). Elution with 5 EtOAc.c~clol ,_Aa~e (1:4) ~ava the title comPound as a beige solid (232mg). H n.m.r. (CDCI3) 7.82~ (1 H,br s), 7.4~ (1 H,d), 7.09~ (1 H,m), 6.73~ (1 H,d), 6.52 (1 H,m), 4.67~ (2H,t), 3.32~ (2H,t).
,. ", 4 ~0 2.3.7.8-T0trahvdro-1H-furor2,3~1indole 1"' ,..- ' ' 3 (275mg) was dissolved in borane THF complex (1M solution, 2.6ml) and was stirred at 0C under N2, then trifluoroacetic acid (2.6ml) was added drûpwise. Stirring was ",. :.,t~ d at 0C for 45min and saturated potassium carbonate solution added. The mixture was extracted with EtOAc 15 (2x30ml). The dried extracts were ~ uldt~d and the residue ll " a~ ed on silica gel (309). Elution with EtOAc:cy.lul~ "e (1:2) gave the title comDound as a pale brown oil, which solidified (215rng), m.p. 48-50C
T.l.c. EtOAc:c~.,lul ,~Aa"e (1:2) Rf 0.25.
I~, ,.. 5 (2.3.7.8-Tetrahvdro-1H-furor2.3~1indol-1-vl~ac, tu,,' ile A mixture of II~ edidl~z 4 (~22mg), i~uac~,:ull' ile (0.06ml) and potassium carbonate (105mg) in methyl isobutyl ketone (5ml) was heated to reflux, under N2, for 18h. The cooled miAture was ~al litiull~d between 2N Na2C03 (20ml) and EtOAc (2x30ml). The dried extracts were evaporated and the residue u~ qJl,ed on silica gel (359). Elution with EtOAc:cyulul~,Ad"e (1:3) gave the title comPound as a beige solid (123mg), m.p. 122-4C.
T.l.c. EtOAc:c~-,lul l_Aell ,e (1:2) Rf 0.37.
Il,l~:""~ 6 (7.8-Dihvdro-1 H-furor2,3-alindol-1-vl)ac~
To a stirred solution of II~ llll " ' 3 (227mg) in dry DMF (8ml), was added sodium hydride (60% in oil, 85mg). The mixture was stirred for 0.5h and then 35 I,lu,ua~ù,.' il~ (0.13ml) was added dropwise. The mixture was then left to W0 95117405 ~ /~, I.'Ct-~
21 79~02 stand at 20C for 2 days and was then ~dl -'' Ied between 2N Na2C03 solution (60ml) and EtOAc (2x70ml). The dried extracts were o~_,,u,, ' ' and the residue ~ d~l led on silica gel (409). Elution with EtOA-,.cy..lul,e,.d"e (1:3) gave the title comDound as an off-white solid ~109mg).
1 H n.m.r. (CDCI3) 7.38~ (1 H,d), 6.9~ (1 H,d), 6.77~ (1_,d), 6.53~ (1 H,d), 5.04O
(2~,s), 4.70~ (2H,t), 3.65 (2H,t).
Ille;l;_~ 7 2-(2.3.7.8-Tetrahvdro-1 H-furor2,3~1indol-1-yl)ethvlamine (a) A solution of ll,~,,,, " 6 (160mg) in dry THF (5ml) was treated with borane THF complex (1M in THF, 8ml) and was stirred, under N2, at 20C for 18h. The mixture was then cooled (0C) and trifluoroacetic acid (5ml) added.
After a further 30min saturated potassium carbonate solution was added, dropwise initially, and then the mixture was extracted with EtOAc (2x40ml). The dried extracts were evaporated and IJllul ' _ dpl,ed on silica gel (209).
Elution with System A (100:8:1) gave the title comPound as a pale brov,/n semi-solid (80mg).
1H n.m.r.(CDC13) 6.82~ (1H,d), 6.180 (1H,d), 4.52~ (2_,t), 3.37~ (2_,t), 3.32-3.2 ~ (4H,2xt), 2.97-2.87~ (4~,2xt), 1.8~ (2H,br s).
(b) To a stirred, refluxing, solution of Illlell"e~' 5 (203mg) in dry THF (10ml)was added dropwise borane THF complex (1M solution, 3ml). Heating was "~_;"t_;"e~ for 5h and then the mixture was cooled, and methanol (3ml) added, cautiously at first. 2N HCI (3ml) was then added, and the mixture heated to reflux for a further 1h. The cooled mixture was then ~d,litiolled between saturated K2CO3 (40ml) and EtOAc (2x35ml). The dried extracts were u~"~ and the residue l,hlullldtu~ld~Jlled on silica gel (259). Elution with System A (100:8:1 ) gave the title comPound as a pale yellow oil wnich solidified (166mg). The n.m.r. data for this solid was cunsi~te,,l with that for the same compound prepared in part (a) above.
Il, ", 8 Chroman-5-vl-(2.2~i_11~u~j c~ I)-amine B.~ 4~ l lJJè diethyl acetal (11 .8ml) was added to a mixture of chroman-5-yl-amine (5.859) (prepared according to J. I I_t~"u~ ,lic Chem., (1973), Vol 10 W0951174fl5 ~ 21 79402 ~ r~
. .

(4) page 623), and potassium carbonate (10.849) in dry DMF (70ml) at room Itl".,Ucl~ e under N2. The mixture was heated at 100C for 60h. The cooled mixture was pdl'''' led between water (800mi) and ether (3x200ml). The combined organic extracts were washed with Llill~h ~ 1:1 t2x200ml) snd 5 dried. The solvent was e._,~u~_' ' and the residue purified by flash column ~ lUI11.4tVyld~ on siiica. Elution with c~.lull ~ .JI acetate 6:1 gave the title comDound as a pale yellow oil (8.0~).
T.l.c.SiO2 c~l,lul l_Aell I~ ,JI acetate 6:1, Rf 0.35.
10 1~, ", 9 N-Chroman-5-vl-N-(2.2-diethoxY-ethvl)-2.2.2-trifluoro-ac~l~" ~idt~
Trifluoroacetic anhydride (4.67ml) in dry ~il,l,l~,u,,,t,~l,d,,e (10ml) was added dropwise to a solution of ll l' ", " ' 8 (7.g99) and ~, i_;~,)'~.. ,.;"e (4.62ml) in dry di~illlulullle~lldlle (190ml) at 0C under N2. The mixture was allowed to warm to 15 room temperature and stirred for 2h. The mixture was washed with water (2x100ml) and dried. The solvent was evaporated to sive the title comDound as a pale yellow oil (10.359).
. T.~.c.cy~ Ad"¢~u~ rl acetate (6:1), Rf 0.6 20 Ill~ did~ 10 1 ,7,8,9-Tetrahvdro-Dvranor2,3~1indole A solution of lll' ,.. ' ' 9 (0.19) in dry di~,l.lu,u,.._l:,d"e (1ml) was added dropwise to a solution of TFA (1 .5ml) and TFM (1 .Oml) in dr,Y ~iul ll-,l u",_l: Idl ,e (10ml) at 0C under N2. The mixture was allowed to warm to room temperature and stirred for 20h. The solution was cooled and basified to pH12 with 5%
potassium hydroxide in methanol. The mixture was stirred for 5min, then ~._,,u, ' ' The residue was pd,li;;u,,ed between water (15ml) and ethyl acetate (3x10ml). The combined organic extracts were washed with brine (1x20ml) and dried. The solvent was evaporated and the residue purified by 30 flash l,lllu~l~ ' c, d,lJIly on silica. Elution with cy.~lulICIAI~ U~ Iyl acetate 10:1 aave the title comPound as a colourless solid (21.7mg).
T.l.C cy.,lul I~Adl l_~.l lyl acetate (4:1), Rf 0.35.
11,~.,lll " ' 11

3~ 1,2,3,7.8.3 H~Adl.~l.u-DYranor2.3-alindo~e WO9511740~ 2 1 79402 r~ c~n Borane (1 .OM in THF; 5mlj was added dropwise to a solution of ll l ~lle~;dta 10(434mg) in dry THF (10ml) at 0C under N2. Trifluoroacetic acid (32ml) was then added dropwise and the mixture stirred for 10min at 0C. 2N sodium hydroxide (8ml) was added dropwise cautiously at 0C to pH12. The mixture 5 was then ~ali" ~éd between water (15ml) and ethyl acetate (3x15ml). The combined organic extracts were washed with brine (1x20ml) and dried. The solvent was 6._, _' ' and the mixture was purified by flash column d"l _ a~ on silica. Elution with cydul l_~all~ yl acetate 4:1 gave the title comDound as a colourless gum (222mg).
T.l.c.Ethyl '~.,lullc~alle(4:1), RfO.3.
11l' .Ille~ial~ 12 (2~3~8~9-Tetrahvdro-7H-Dyranor2~3-qlindol-1-vl)-d~
t~ , (0.11ml) was added to a mixture of IIILe~ " 11 (222mg) and potassium carbonate (210mg) in MIBK (10ml) at room lelll~Jel ~e. The mixture was heated under reflux for 5h, cooled to room lelll~Jel_ ~re, then pdli"' ,ed between water (15ml) and ethyl acetate (3x15ml). The combined organic extracts were washed with brine (1x20ml) and dried (MgSO4). The solvent was evaporated and the residue purified by flash column ,I"ulll _ a~Jlly on silica. Elution with c~ululle~dllo~l Iyl acetate 5:1 gave the title comDound as a colourless gum which crystallised on standing (0.259).
T.l.c.c~ eA~"e/e~l,yl acetate (3:1), Rf 0.37.
Il~ ",adi~.t~ 13 2-~2.3.8.9-Tetrahvdro-7H-DYranor2.3-q1indol-1-vl)-ethvlamine Borane (1.0M; 2.27ml) was added dropwise to a solution of ll , . " 12 (243mg) in dry THF (5ml) at 0C under N2. The solution was heated und~r reflux for 3h, cooled to 0C and methanol (1 ml) was added cautiously dropwise until effervessing ceased. 2N HCI (2ml) was added (to pH1) and the mixture 30 heated under reflux for 15min, cooled to ûC and basified to pH12 with 2N NaOH (3ml). The mixture was ~dlIi~iulled between water (10ml) and ethyl acetate (3x15ml). The combined organic extracts were washed with brine (1x15ml) and dried. The solvent was L~ul ' :1 and the residue purified by flash column ulllull _ d~lly on silica. Elution with WO 9~/17405 ,. :~ 1 2 1 7 9 ~ 0 2 I ~,11~ . I.'C 17'~ ~

di~ UlU.~.J~hdll~/U'Idll~ ull;d 100:8:1 gave the title comr~ound as a colourless gum (160mg~.
T.l.c.Di~ lulu.l,Jt.~,a,,uJu~lldllol/d,,,,,,ull;~ (100:8:1), Rf 0.3.
Il,~ ".-" ' 14 2.3.7.8-Tetrahvdro-1 H-furo~2,3-qlindole-1 ~d, Lakl~l "lala To a stirred solution of ll ' n~ ~ 4 (320mg) in formic acid (3ml) was added dropwise acetic anhydride (1ml). Th~ mixture was thsn heated to ca. 60C for 20min. The mixture was then added cautiously to 2N Na2CO3, and was extracted into EtOAc. CVd~Jula~;ul- of the dried extract gave an off-white solid(360mg).
T.l.c.(SiO2) CH2CI2:EtOH:NH3; 400:8:1, Rf 0.29 IlIte~ Jid~tl 15 5-Chloro-2.3.7.8-tetrahvdro-1H-furor2.3-qlindole-1-Cdl uald~ d~7 A stirred solution of ll,le, . ' 14 (180mg) in glacial ac~tic acid (4ml) was treated with N-chlorosuccinimide (140mg) and was stirred for 7h. The mixture was pdl~iliull~d b~tween 2NNa2CO3 and EtOAc. Evaporation of the dried extracts gave a grey solid (218mg).
T.l.c.(SiO2)EtOAc.c~.,lul,~Ad,~e, 1:1, RfO.19 ..",ed;dte: 16 5-Chloro-2.3.7.8-tetrahYdro-1 H-furor2.3-qlindole rl"edidl~ 15 (210mg) was dissolved in methanol (5ml) and 2N HCI (1ml) added. The mixture was stirred at 20C for 18h, then at reflux for 1h. The mixture was allowed to cool, and the methanol c,/_,,." ' ' The residue was then pd,liLiu,,ed between 2N Na2CO3 and EtOAc. The dried extracts were ~,/_,,u, ' ~ to give a brown solid (166mg).
T.l.c.(SiO2) EtOAc:c~ Adll~, 1 1, Rf 0.36 Il, ",edidtl: 17 (5-Chloro-2.3.7.8 t~_t, dl l ~/dl u-1 H-furor2 3-qlindol-1 -vl)-ac~u"i~, ;'~i A stinred solution of ll~ did~ 16 (165mg), i~dûac~u,,i~ (û.073ml) and potassium carbonate (140mg) in methyl isobutyl ketone (10ml) was heated to 35 reflux for 18h under N2. The mixture was cooled, and ~al~iiiu~ d ~etween ~ WO9S/17405 ~ 217~402 P~ rt~

2N Na2CO3 and EtOAc. The dried eAtracts were u~a~u, ' ~ to give a dark residue which was ~,11ll ' ~, ~,ùl~ed on silica gel. Elution with CH2CI2:EtOH:NH3; 400:8:1 gave a pale brown solid (155mg).
T.l.c.tSiO2) CH2CI2:EtOH:NH3; 400:8:1, Rf 0.67 1~, (r, 1 8 2-(5-Chloro-2.3.7.8 t~t~dl~lu-1H-furor2~3~lindol-1-yl)-ethvlamine A miAture of ll ' I~le~ 17 (150mg) in dry THF (5ml) Cu"'_;.,;"~ borane THF
(1M in THF, 1.9ml) was heated to refluA, under N2, for 18h. The miAture was cooled, and methanol (2ml) added dropwise. 2N HCI (4ml) was then added, and the miAture heated to refluA for a further 1h. After cooling, the miAture was ~lliliOIled between saturated K2CO3 and EtOAc. The dried e)~tracts were evaporated, and the red crystalline solid cl ", ' _ ~yl ,ed on silica gel. Elution with CH2CI2:EtOH:NH3; 100:8:1 ~ave a pink crystalline solid (110mg).
T.l.c.(SiO2) CH2CI2:EtOH:NH3; 100:8:1, Rf 0.44 Il.' ,ne"' 19 Cv~luulu~dl~ecdli,~A~ acid (cv.,lù~,u,,d"ecd,ùu";l)-r2--(2,3,7,8-tetrahvdro-1H--furor2.3~lindol-1 -vl)-ethvll-amide To a cold (0C) stirred solution of lll' - li ' 7 (111mg) in CH2CI2 (10ml) and diisopropylethylamine (0.14ml) was added c~/~,lu,ul u,uyl carbonyl chloride (0.074ml) dropwise under N2. The cooling bath was removed and the miAture stirred at 20C for 18h. The miAture was ~d,liliu,,ed between 2N Na2CO3 and EtOAc. The dried eA~tracts were ~.."o, ' ' and the residue ul~u~ d~Jlled on silica gel. Elution with EtO.~.c~ lul l_Abl ,æ; 1:4 gave a colourless oil (141 mg) which slowly crystallised.
T.l.c.(SiO2) CH2CI2:EtOH:NH3; 200:8:1, Rf 0.86 Il ~t~,. ", . " ' 20 ~2.2-Di_ll IUA~V ~;l n~l)-(2~3-dihvdro-benzofuran 4-vl)-amine A miAture of 2,3-dihydro-benzofuran ~ yl_."i"e (ylepdldliOI~. I. Hetereocvclic Chem., 18, 1333 (1980)) (4.349), potassium CdlbOll '- (8.879) and bromo awt~lJ~:l,yde diethyl acetal (9.7ml) in dry DMF (60ml) was heated to 100C for 2 days under . The miAture was cooled and was pd(titiul ,ed between v~ater and 35 ethyl acetate. The dried eAtracts were ~ ,u, d~ed and the residue WO 95117405 , 2 ~ 7 9 4 0 ~ P~ c ~ ~
æ
.,11l. . ' _ a~,l,ed on silica gel t2509). Elution with ethyl 1:4 gâve the fitle comDound as a pale yellow oil (4.959).
T.l.c.EtO.~.~,lul Iè 1:1, Rf 0.73.
Analysis Found:C,66.8; H,8.5; N,5.35;
C14H2,NO3 requires:C,66.9; H,8.4; N,5.55%
" ' 21 N-(2.2-DiethoAv-ethvl)-N-(2.3-dihvdro-benzofuran-4-vl)-2.2.2-trifluoro-~ld" li~eTrifluoroacetic anhydride (4.1 2ml) was added dropwise to a cooled (0C) stirring solution of the i"' Ille~i~.t~, 20 (6 679) and triethylamine (4 06ml) in di~ lulullle~llal~e (100ml) under nitrogen The miAture was warmed to room le~ Jel ' Ire and stirred for 1 '~h The reaction mixture was pdl ~iLiul ltLd between water and ,Ij~,lllulul"Jtl,d"è The aqueous phase was ro ~Alla~,~e~ with ~i.,hlulullle~lldlle. The combined organic layers were dried, evaporated and 15 ,,I"u" ' ~, d~llèd on silica gel eluting with ethyl acetate:c~,lul,eAd"e 1:9 gave the title comDound (8 319) as a yellow oil T.l.c.C~,-,lùll~Aàl,è.EtOAc(4:1), RfO.38.
Analysis Found:C,55.3û; H,5.74; N,3.96;
C16H20F3NO4 requires:C,55.33; H,5.8; N,4.03%
,,Ille.lidte22 7.8-Dihvdro-1 H-furor2,3~lindole A solution of the i, ' Illedia~e 21 (8.279) in .li~l,lu,u",e~l,ane (8ûml) was added dropwise to a stirred solution of trifluoroacetic acid (80ml) and trifluoroacetic anhydride (53ml) in di.,l,lu,u,,,_;hd,,e (800ml) at 0C under nitrogen. This waswarmed to room temperature and stirred for 20h. The cooled reaction miAture was basified with 2N sodium hydroxide and then stirred for 1'~h at room tu,ll~Jel ' l~e. The organic phase was separated and the aqueous layer was re-eAtracted with di~lllululll-l:lalle The Gombined orgsnic phases were dried, c. "u, .t~,~ and ul IlUllld~Uyl d,ul led on silica gel eluting with EtOAC Cyclul l~Adl le (1:9) gave the title comPound as a beige solid (2 69).
T.l.C.Gy~.lùl~l~Aal lè.~A. Iyl acetate 7:3, Rf 0.43.
Analysis Found:C,75.31; H,5.65; N,8.62;
C,OH~,NO requires:C,75 45; H,5.70; N,8.80%

WO 95117405 -. . r~,-".. , 1~ n ~ 21 79402 ExamDle 1 N-r2-t2.3.8.9-Tetrahvdro-7H-Pvranor2.3-alindol-1 -vl)-ethYll-ac~ta" ,ida Acetic anhydride (0.104ml) was added to a solution of the ll' ",~:didta 13 (160mg) and pyridine (0.12ml) in dry THF (4ml) at 0C under N2. The mixture was allowed to warm to room te~ e and stirred for 3h. The solvent was ~_"u, ' ~ and the residue purified by flash column ~,1"~", _ a,~ on silica.
Elution with ethyl acetate aave the title comDound as colourless crystals (151mg), m.p. 91-93C.
T.l.c.Ethyl acetate, Rf 0.2.
ExamPle 2 N-(2-(2. 3.8.9-Tetrahvdro-7H-Pvranor2~ 3-alindol-1 -vl)-ethvll-ace ~dl "id~
~1 ~d~ u~ lul i~e Ethereal HCI (û.25ml) was added dropwise to a solution of the title compound of Example 1 (56mg) in ethanol (2ml) at 0C under N2. The solvent was evaporated and the residue triturated under ether (2x1ml). The solvent was decanted to give the title comPound as a colourless solid (63mg), m.p. 179-181C.
Analysis Found:C,58.6; H,7.5; N,8.95;
C~sH20N2O2.HCI requires:C,58.6; H,7.3; N,9.1%
1H N.m.r. (CD30D; ~) 7.2~ (~,d), 6.9~ (~, d), 4.24~ (~,t), 4.07~ (~,t), 3.6 (~,AA'BB'), 3.28~ (j~,t), 2.88~ (2H,t), 2.1-1.95~ (~,m+s) ExamPle 3 N-r2-(2.3.7.8-Tetrahvdro-1 H-furor2.3-alindol-1 -vl)ethvll-ac~td" ,;~e To a stinred solution of ll Ille:did~ 7 (77mg) in dry THF (5ml) COIILaillilly pyridine (0.09ml) was added acetic anhydride (0.û6ml). After 18h at 2ûC the mixture was pdl ~itio,~ed bet veen 2N Na2C03 (3ûml) and EtOAc (2x30ml). The dried extracts were ~ u~ ' ~ and the residue ~,IIlu~ t~Jyld,ull~d on silica gel (209). Elution with System A (200:8:1) gave the title compound as a colourless crystalline solid (56mg), m.p. 126-7C.
T.l.c. System A (100:8:1 ) Rf 0.42.
Example 4 WO95/17405 2 1 79402 .~ cl~n ~ . . ..~

N-r2-(2.3.7.8-Tetrahvdro-1 H-furor2.3-qlindol-1 -Yi)-ethvll-r~ ,;
I.fd~u~.l ,lu,ide Th~ title compound of Example 3 (334mg) was dissolved in ethyl acetate (20ml) and was treated with ether~al HCI (1.35ml). This was stirred at room It""~,t" ' ~re for 2h and then the solvent was evaporated to give the title comDound as a pale gr~en powder (383mg), m.p. 152-154C.
T.l.c. Systern A 1û0:8:1, Rf û.41.
Analysis Found:C,59.45; H,7.15; N,9.55; Cl,12.8;
C14H18N2O2.HCI requires:C,59.45; H,6.75; N,9.9; Cl,12.55%
1û
Example 5 N-r2-(5-Chloro-2.3.7.8-~i,dl,~lu-1H-furor2.3-qlindol-1-vl)-ethvll-ac~ Ld,,,ide A solution of ll.' ",~didta 18 (107mg) in dry THF (5ml) and dry pyridine (0.11ml) was treated with acetic anhydride (û.û85ml) and left for 2 days at 20Cunder N2. The mixture was ~alli~iull~d between 2N Na2CO3 and EtOAc. The dried extracts were evaporated, and the residue ~ dpl~ed on silica gel.
Elution with CH2CI2:EtOH:NH3; 200:8:1 gave the titl~ comPound as a colourless crystalline solid (114mq), m.p. 1479C.
Assay Found:C,60.15; H,6.35; N,1û.05;
C,4H17CIN2O2 requires:C,59.9; H,6.1; N,10.0%
T.l.c.(SiO2) CH2C12:EtOH:NH3; 1ûû:8:1, Rf û.69 Example 6 Cv-,lu~l uPal l~Cal l,û~,;c acid r2-(2.3.7.8 t~t, dl .fdl ù-1 H-furor2.3-qlindol-1 -vl)-ethYll-amide Il, ", ' ' 19 (140mg) was stirred in methanol (10ml) and 2N NaOH (4ml) at 20C under N2 for 18h, and then at reflux for 1h. The mixture was diluted with water and extracted with EtOAc. The dried extracts were ef_"~l al~d giving the ~itle comr~ound as a colourless solid (111mg), m.p. 147-9C.
3û Assay Found:C,70.9; H,7.45; N,10.15;
C1~,H20N2O2 requires: C,70.55; H,7.4; N, 10.3%
T.l.c (SiO2) CH2CI2:EtOH:NH3; 200:8:1, RF0.48 Example 7 N-r2-(2.3.7.8-Tetrahvdro-1H-furor2.3~lindol-1-Yl)~thvll~ct,le"nidt .

WO 9S/17405 ., ~ .1, I.'C:

A mixture of ll,- n~ , 4 (50mg), r ' ~m iodide (19) and N-(2-1,1 ll~luut~"~l) ' i~ (96mg) in acetone (5ml) was heated to reflux for 2 days.
The cooled mixture was pa~ d between water and ethyl acetate. The ex~racts were dried, and ~:, ' i, and the residue ,11l Ullld~ ~UI a~l ,ed on silica gel. Elution with CH2CI2:EtOH:NH3; 400:8:1 gave a sample of desired material (69mg).
T.l.G(SjO2) System A; 100:8:1, Rf 0.42 'Hn~mr agreeswithb~ ulllllelllfor " "dti~uroutesof~ ,d,dtio,l.
6.85~ (~,d), 6.2~ (~,d), 5.86~ (~,brs), 4.52~ (j~,t), 3.5-3.3~ (~,m), 3.22 (~,t), 2.93~ (~,t), 2.0~ (3H,s) Examole 8 Compounds of formula (I) have been shown to exhibit high affinity and selectivity for binding to melatonin receptors in chicken retinal Ille~ L,Iall~s, 15 measured according to the methods of Dubocovich and Takahashi (Proc. Natl.
Acad. Sci. (1988), 84, 3916-3820). The compounds of fommula (I) have either melatonin agonist or bllla~ull;~.l activity as dt:lllUll~LIdte:~ in rabbit retina, according to the methods of Dubocovich (J. Pl,a""a~l. Exp. Therap. (1985), ~, 395-401). The results obbined for particular compounds according to the 20 present invention are as follows:
Comoound Chicken retina Ki (nM) Rabbit retina ICsrl (nM) Example 2 4.92 0.950 Example 3 0.42 û.040 Example 5 3.21 0.004 Example 6 1.68 0.200 Exam~le 9 30 Compounds of formula (I) have been included in pharmacy fommulations, and details of such fommulations are given below.

-woss/1740s . ~ 2179402 P~ c ~

TABLETS FOR ORAL ADMiNlSTRATlON
A.Direct Cu",v,~ , mg/tablet Active ingredient 49.0 Anhydrous Lactose 55.2 r 1 u~ e cellulose 37.5 ~." ' " ,;s.~d maize starch 7.5 Magnesium stearate û.8 The active ingredient was sievad and blended with the excipients. The resultant 5 mix was cu.,,p, t:~sed into tablets using a tablet machine fitted with d,U,~JI U~ y sized concave punches.
B. Wet Granulation mg/tablet Active ingredient 7.û
Lactose BP 146.5 Starch BP 30.0 Pr~y~laii"is~d Maize Sbrch BP 15.0 Magnesium Stearate BP 1.5 CUIII~JI e a~iOI I weight 200.0 The active ingredient was sieved through a suitable sieve and blended with lactose, starch and p~ la~illia~d maize starch. Suitable volumes of purified water were added and the powders were granulated. After drying, the granules were screened and blended with the magnesium stearate. The granules were 15 then c~lll~J,e3~ - ;1 into tablets using suitable diameter punches.
Tablets of other strengths may be prepared by for example altering the ratio of active ingredient to lactose or the cu~y~iull weight and using punches to suit.

WO 95/17405 ; ; ~ P~ o ~-n ~ ` ` 2 1 794~2 Unit formula Active i"yl ediel ,Uld~ se granule~ 93.0 '' u~' " ,a cellulose Ph Eur 5.5 cru~ dl l l l ~ s 9 Sodium USNF 1.0 Magnesium Stearate Ph Eur 0.5 ~ ActiYe i"y~ ediel ,UIc,ulu~e granule mg Active ingredient 140.0 Lactose Ph Eur 170 mesh 14û.0 Purified water Ph Eur qs +

+ The water does not appear in the final product. Typical range 100-1409 per kg of blend.
The sctive ingredient and lactose wQre mixed together and granulated by the 10 addition of purified water. The granules obtained after mixing were dried andpassed through a screen, and the resulting granules were then mixed with the other tablet core excipients. The mix is cc."",, eased into tablets.
The tablets may be film coated with suitable film-fomling materials, such as 15 II~IUA~,UIUPYI ..._lh~ os~, using standard techniques. ~.' IldlilUIy the tablets may be sugar coated, or enteric coated.
Coating Suspension % w/w I IY~)UAY~JIU~UYI ",_I~.;lu~llulose Ph Eur 10.0 Opaspray white # 5 0 Purified water Ph Eur to 1 OO.O+f -WO 95117405 2 1 7 9 4 0 2 , ~llr ~ . ~ c +I The water does not appear in the final product. The maximum Ult:ull "
weight of solids applied during coating is 11mg/tablet.
# Opaspray white is a proprietory film coating suspension, '~ mbl~ fromS Colorcon Ltd, UK, which contains hJ~Iux~lu~ L~lyl " ~ ce and titanium dioxide.
The tablets were film coated using the coating suspension in conventional film coating equipment.
1û
EFFERVESCENT TABLET
mg/tablet Active ingredient 14û.0mg Sodium L,i~l Lù, ,~tt, . 656.4mg Monosodium citrate anhydrous 659.5mg Aspartame 40.0mg Polyvinylpyrrolidone 32.ûmg Sodium benzoate 48.ûmg Orange flavour 16.ûmg Lemon flavour 8.0mg Absolute alcohol for granulation The active ingredient, anhydrous monosodium citrate, sodium bicdl~u,. '~ and 15 ~apelll~",a were mixed together and granulated by the addition of a solution of the polyv;. I~ ' ' ,e in the alcohol. The granules obtained after mixing were dried and passed through a screen, and the resultin~ granules were then mixed with the sodium benzoate and flavourings. The ~ranulated material was cull,,u,~aaed into tablets using a machine fitted with 20mm punches.
A rotary machine fiHed with 20mm punches may also be used for tabletting.

~ wo 95/17405 ~ 2 1 7 9 4 0 2 I ~ .'C: -LIQUID AND CAPSULE FORMULATIONS FQR ORAL ADMINISTRATION
Liquid formulations were prepared by slow addition of active i. .y. t,~ic, I~ into the other i"y, ~ "ts at 35-50C with constant mixing (amounts are given as 5p~,~"t~ge 'NIW).
Example A B
Active ingredient 18.2 18.2 Oleic acid 60.985 68.485 Polyethylene glycol 600 7.3 7.3 Propylene glycol 6.0 6.0 ~.ly~ , 80 7.5 Ascorbyl palmitate 0.015 0.015 The liquid formulations were filled into hard gelatin capsules each capsule c~" ,;"9 25mg of active ingredient.

mg/capsule Active ingredient 49.0 ~Starch 1500 150.0 Magnesium Stearate BP 1.0 Fill weight 200.0 ~ A form of directly cu" ,p, ~:~aiLle starch.
15 The active ingredient was sieved and blended with the excipients. The mix wasfilled into size No. 2 hard yelatin capsules using suitable machinery. Other doses may be prepared by altering the fill weight and if necessary changing the capsule size to suit.

WO 95/17405 - , ~ 2 1 7 9 4 0 2 P~ 1/~ L~ --n ~
....~

SYRUP
Sucrose Free r~e~e"' ' ~ mg/5ml dose Active insredient 49 0 U~f~lU~ .. Jt~ In~e USP 22 5 (viscosity type 40ûO) Buffer Flsvour ) asrequired Colour r, eael~/d~
er Purified water BP to 5.0ml The l,)~lu~,,,upylmethylcellulose was dispersed in hot water, cooled and then 5 mixed with an aqueous solution ~"~;. ,;"9 the 3ctive in~redient and the other wlll~Jullel,l;, of the formulation. The resultdnt solution was adjusted to volume and mixed. The syrup was clarified by filtration.
SUSPENSION
1û
mgl5ml dose Active ingredient 49.û
Aluminium Illo~ eclld~e 75.0 S~. ' li"~ agent ) as required Flavour Colour Fl duliul ~ ' ~ coconut oil to 5.ûml The aluminium lI~Un~ledl ' was dispersed in about 9û% of the rld~AiUlldied roconut oil. The resulting suspension was heated to 115C while stirring and then cooled. The _.._ ' ,i"g agent, flavour and colour were added and the ~ W095/i7405 ~ 2 l 79~U2 ~ c:

active ingredient was suitably dispersed. The suspension was made up to Yolume with the remaining r~ ;JI ' 1 coconut oil and mixed.
SUB-LINGUAL TABLET
(mg/tablet) Active illyledi_.. Uk,~,lu~e granule~ 49.û
CLnlllJleaaiLlll3 sugar NF 5b.5 Magnesium Stearate BP 0.5 C~ SaiOl~ Weight 100.0 The active ingredient was sieved through a suitable sieve, blended with the excipients and w,,,~ c,~ using suitable punches. Tablets of other strengths may be prepared by altering either the ratio of active ingredient to ~A~ ie, Ita or 10 the w" ,,~" eaa;~JI I weight and using punches to suit.
SUPPOSITORY FOR RECTAL ADMINISTRATION
Active ingredient 49.0mg ~Witepsol W32 1.09 5 ~ A rJ~ JI ielell y grade of Adeps Solidus Ph Eur A suspension of the active ingredient in molten Witepsol was prepared and filled using suitable machinery, into 19 size c, ~, F y moulds.

WO95117405 2 1 7 9 4 0 2 1~l/~ I'C ~n INJECTION FOR SUBCUTANEOUS ADMINISTRATION
mg/ml Active ingredient 0.896 Sodium Chloride Intravenous to 1 ml infusion, BP, 0.9% w/v Batch size 2500ml The active ingredient was dissolved in a portion of the Sodium Chloride 5 intravenous Infusion, the solution made to volume with the Sodium Chloride Intravenous Infusion, and the solution thoroughly mixed. The solution was filledinto clear, Type 1, glass 1 ml ampoules and sealed by fusion of the glass under a nitrogen or air h~ ræ The ampoules were sterilised by ~ i"y at 121C for not less than 15 minutes. All~ ti~Qly the solution may be sterilised 10 by filtration prior to filling ~ , ' 'Iy into ampoules.
FOR INHALATION
Inhalation Cartrid~es " ,~,~, ll i~,a~
Active ingredient (I~i.. lu~ cd) 0.56 Lactose BP 25.00 The active ingredient was ",i~ u, 1;_3d in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer. The powder blend was filled into No 3 hard gelatin capsules on a suitable encapsulating machine. The contents of the cartridges were ~d~ using a powder inhaler such as the Glaxo Rotahaler.

wo 95/17405 r ~ r ~

Metered Dose Pressurised Aerosol Suspension Aerosol ",~" ' ~d Per can dose Active ingredient (~ u~ ~;c~a~) 0.280 73.92mg Oleic Acid BP 0.020 5.28mg Tl iul llul I ~ 1 ul I le~l Idl ,e BP 23.64 5.679 Diul~luludillu~lull~e~lld~ BP 61.25 14.709 The active ingredient was Illi~ulli~e~ in a fluid energy mill to a fine particle size 5 range. The oleic acid was mixed with the lli~ lululll_lh~ at a t~:",e:~l Ire of 10-15C and the Illi-,lul~;s~d drug was mixed into the solution with a high shear mixer. The suspension was metered into aluminium aerosol cans and suitable metering valves, delivering 85mg of suspension, were crimped onto the cans and the ~i.,l~lulu~illu~lulll_; ldll~ was pressure filled into the cdns through the 10 valves.
NASAL SPRAY
% wlv Active ingredient 7.û
Sodium Chloride BP 0.9 Purified Water BP to 100 Shot Weight 1 OOmg (equivalent to 7mg active i"yl ~di_. Il) 15 The active ingredient and sodium chloride were dissolved in a portion of the water, the solution made to volume with the water and the solution thoroughly mixed.
The pH may be adjusted to facilitate solution of the active ingredient, using acid 20 or alkali and/or ~llh~Pql~Pntly adjusted ideally to near neutrality taking into account the pH for optimum stability. Altt:llldti~ulj, suitable bu~fer salts may be WO 95117405 2 1 7 9 4 0 2 P~ c ~n .. . .

used. The solution may be preserved with, for example, ~t, " ,i,-m r,hloride and pl)~ ,yl alcohol, for a multi-dose nasal spray.

Claims (13)

1. A compound of formula (l) (l) wherein R1 is hydrogen, halogen or C1-6 alkyl;
R2 is a group of formula -CR3R4(CH2)pNR5COR6;
R3, R4 and R5, which may be the same or different, are hydrogen or C1-6alkyl;
R6 is C1-6alkyl or C3-7 cycloalkyl;
n is an integer of 2,3 or 4;
p is an integer of 1,2,3 or 4;
and pharmaceutically acceptable salts and solvates thereof.

2. A compound of formula (la) (1a) wherein R1 is hydrogen, halogen or C1-6 alkyl;
R2 is a group of formula -CR3R4(CH2)pNR5COR6;
R3, R4 and R5, which may be the same or different, are hydrogen or C1-6alkyl;
R6 is C1-6alkyl or C3-7 cycloalkyl;
p is an integer of 1,2,3 or 4;
and pharmaceutically salts and solvates thereof.

3. A compound according to Claim 1 or 2, wherein R2 represents a group -CR3R4(CH2)pNHCOR6 wherein R3 and R4 each independently represent hydrogen or C1-3 alkyl, p is an integer of 1 or 2, and R6 is C1-3 alkyl or C3-5 cycloalkyl.

4. A compound according to any of claims 1 to 3, wherein R1 is selected from the group consisting of hydrogen, chlorine and C1-3 alkyl.

5. N-[2-(2,3,8,9-Tetrahydro-7H-pyrano[2,3-g]indol-1-yl)-ethyl]-acetamide;
N-[2-(5-Chloro-2,3,7,8-tetrahydro-1H-furo[2,3-g]indol-1-yl)-ethyl]-acetamide;
Cyclopropanecarboxylic acid [2-(2,3,7,8-tetrahydro-1H-furo[2,3-g]indol-1-yl)-ethyl]-amide;
and pharmaceutically acceptable salts and solvates thereof.

6. N-[2-(2,3,7,8-Tetrahydro-1H-furo[2,3-g]indol-1-yl)-ethyl]-acetamide and pharmaceutically acceptable salts and solvates thereof.

7. A pharmaceutical formulation comprising a compound of formula (l) according to any of claims 1 to 6, together with one or more pharmaceutically acceptable carriers therefor.

8. A process of preparing a pharmaceutical formulation comprising a compound of formula (l) according to any of claims 1 to 6, together with one or more pharmaceutically acceptable carriers therefor, which process comprises mixing said compound of formula (l) together with said one or more pharmaceutically acceptable carriers therefor.

9. A compound of formula (l) according to any of Claims 1 to 6, for use in therapy.

10. A compound of formula (l) according to any of Claims 1 to 6, for use in the preparation of a medicament for use in the treatment of conditions associated with a disturbed functioning of the melatonin system.

11. A method of treating a mammal, including man, comprising administration of an effective amount of a compound of formula (I) according to any of Claims 1 to 6, for the treatment of conditions associated with a disturbed functioning of the melatonin system.

12. A process of preparing a compound of formula (I) according to any of Claims 1 to 6, which process comprises:
(a) acylation of a compound of formula (II) (II) or (b) treating a compound of formula (XII) (XII) with an alkali metal hydroxide;
or (c) alkylation of a compound of formula (IV) (IV)

13. Compounds of formulae (ll), (lll), (lV), (lVa), (V), (Vl), (Vll), (Vlll), (lX), (Xl) and (Xll).